Les fleuves dans l'œuvre romanesque de Jean-Marie Gustave Le Clézio

Relying on Merleau-Ponty's phenomenology of perception and on Mircea Eliade's works on the Sacred and the Profane, this study explores the river as a perceptual space and as the sacred Center in a cosmic vision of the world in twelve of Jean-Marie Gustave Le Clézio's fictional works, from The Interrogation (1963) to Revolutions (2003). In the first chapter, after introducing the field of study, I discuss the relation between the radical subjectivity and the evasiveness of perceiving subjects in Le Clézio's fiction. Next are some thoughts on the relation between Merleau-Ponty's and Le Clézio's ideas. The second chapter studies the river as an experience in the text, first as a topographical space, then as a sound world. The investigations move on to its water as a visual and a tactile phenomenon. Then follows the human use of the river, the (absence of) baths, and the river as a traveling space. The chapter closes with the study of the metaphorical use of the word, occurring mainly in urban space and for phenomena in the sky. The third chapter is organized around the river as the Center of the world in a religious cosmogony, where the river represents the origin of the world and of the human race. The core analysis shows how the middle of the river is a symbolic space of a new beginning. As a sacred space, the river abolishes time as the object of contemplation and as relative immobility from the point of view of a person drifting downstream. The functions of a new beginning and of abolition of time are combined in the symbolic immersions in the water. Finally, the dissertation explores other symbolical spaces, such as the unknown destination of the drift, and the river as the Center of a utopia. The chapter closes with the existential agony as a result of the elimination of the Center in the urban environment. In the final chapter, the river is compared to other watercourses : the creek, the brook and the rapids. The river is more of a spatial entity, whereas the actual water is more important in the smaller watercourses. The river is more common than the other watercourses as a topographical element in the landscape, whereas the minor watercourses invite the characters to a closer contact with their element, in immersions and in drinking their water. Finally, the work situates the rivers in a broader context of different fictional spaces in Le Clézio's text.

Blue mussel beds as biodiversity hotspots on the rocky shores of the northern Baltic Sea

ABSTRACT The Baltic Sea is a vulnerable ecosystem currently undergoing a number of changes, both natural and human induced. The changes are likely to affect the species found on these shores, e.g. their distribution and interactions with other species. Blue mussels (Mytilus trossulus x Mytilus edulis) provide one of the main biogenic hard structures on the shallow shores of the Baltic Sea where they aggregate into dense beds and provide a number of resources for over 40 associated macrofaunal species, thus functioning as ecosystem engineers. The blue mussel, being a marine species, is highly likely to be affected by any changes in sea water salinity, circulation and/or water balance. These changes could trickle down also to affect the associated macrofaunal communities. The aims of this thesis were three-fold: first, I examined and described the macrofaunal communities found within blue mussel patches since the fauna associated with mussel patches had never been described in the study area prior to this thesis. Second, I explored how changes in mussel density, size as well as patch size and shape would affect the mussel communities. Finally, I tested how general landscape theories derived from terrestrial studies function in blue mussel systems. Theories included the structural heterogeneity hypothesis, species-area relationships, edge effects and patch isolation effects. The work shows that blue mussels in the northern Baltic Sea have an indisputable function as diversity hotspots and that the faunal assemblages found in mussel patches are extremely rich and unique. Further on, it shows that changes in mussel biomass, size, patch size and amount of edge have the potential to alter the faunal assemblages and diversity within patches. Finally, it shows that although some landscape theories, such as the structural heterogeneity hypothesis, seem to apply also in blue mussel communities, others cannot be directly applied due to the different prevailing conditions in the study system. This is a pioneering work looking at diversity shaping processes on the rocky shores of the Gulf of Finland, making up over 40% of the total water basin. A focus on niche construction, positive facilitation effects and ecosystem engineering could provide new insights and methods for conservation biology, but before this can be done, we need to fully understand the circumstances under which a species becomes an ecosystem engineer and recognize the systems in which it functions.

Mesoporous silica- and silicon-based materials as carriers for poorly water soluble drugs

New chemical entities with unfavorable water solubility properties are continuously emerging in drug discovery. Without pharmaceutical manipulations inefficient concentrations of these drugs in the systemic circulation are probable. Typically, in order to be absorbed from the gastrointestinal tract, the drug has to be dissolved. Several methods have been developed to improve the dissolution of poorly soluble drugs. In this study, the applicability of different types of mesoporous (pore diameters between 2 and 50 nm) silicon- and silica-based materials as pharmaceutical carriers for poorly water soluble drugs was evaluated. Thermally oxidized and carbonized mesoporous silicon materials, ordered mesoporous silicas MCM-41 and SBA-15, and non-treated mesoporous silicon and silica gel were assessed in the experiments. The characteristic properties of these materials are the narrow pore diameters and the large surface areas up to over 900 m²/g. Loading of poorly water soluble drugs into these pores restricts their crystallization, and thus, improves drug dissolution from the materials as compared to the bulk drug molecules. In addition, the wide surface area provides possibilities for interactions between the loaded substance and the carrier particle, allowing the stabilization of the system. Ibuprofen, indomethacin and furosemide were selected as poorly soluble model drugs in this study. Their solubilities are strongly pH-dependent and the poorest (< 100 µg/ml) at low pH values. The pharmaceutical performance of the studied materials was evaluated by several methods. In this work, drug loading was performed successfully using rotavapor and fluid bed equipment in a larger scale and in a more efficient manner than with the commonly used immersion methods. It was shown that several carrier particle properties, in particular the pore diameter, affect the loading efficiency (typically ~25-40 w-%) and the release rate of the drug from the mesoporous carriers. A wide pore diameter provided easier loading and faster release of the drug. The ordering and length of the pores also affected the efficiency of the drug diffusion. However, these properties can also compensate the effects of each other. The surface treatment of porous silicon was important in stabilizing the system, as the non-treated mesoporous silicon was easily oxidized at room temperature. Different surface chemical treatments changed the hydrophilicity of the porous silicon materials and also the potential interactions between the loaded drug and the particle, which further affected the drug release properties. In all of the studies, it was demonstrated that loading into mesoporous silicon and silica materials improved the dissolution of the poorly soluble drugs as compared to the corresponding bulk compounds (e.g. after 30 min ~2-7 times more drug was dissolved depending on the materials). The release profile of the loaded substances remained similar also after 3 months of storage at 30°C/56% RH. The thermally carbonized mesoporous silicon did not compromise the Caco-2 monolayer integrity in the permeation studies and improved drug permeability was observed. The loaded mesoporous silica materials were also successfully compressed into tablets without compromising their characteristic structural and drug releasing properties. The results of this research indicated that mesoporous silicon/silica-based materials are promising materials to improve the dissolution of poorly water soluble drugs. Their feasibility in pharmaceutical laboratory scale processes was also confirmed in this thesis.

Kohdennetut nanopartikkelit ja isotooppikuvantaminen syövän hoidossa

Syövän diagnostiikassa ja hoidossa nanopartikkelit voivat toimia kuljetinaineina lääke- ja diagnostisille aineille tai nukleiinihappojaksoille. Kantaja-aineeseen voidaan liittää kohdennusmolekyylejä partikkelien passiivista tai aktiivista kohdennusta varten tai radioleima kuvantamista tai radioterapiaa varten. Kantaja-aineiden avulla voidaan parantaa lääkeaineen fysikaalis-kemiallisia ominaisuuksia ja biologista hyötyosuutta, vähentää systeemisiä sivuvaikutuksia, pidentää lääkeaineen puoliintumisaikaa ja siten harventaa annosteluväliä, sekä parantaa lääkeaineen pääsyä kohdekudokseen. Näin voidaan parantaa kemo- ja radioterapian tehoa ja hoidon onnistumisen todennäköisyyttä. Kirjallisuuskatsauksessa perehdytään nanokantajien rooliin syövän hoidossa. Vuosikymmeniä jatkuneesta tutkimuksesta huolimatta vain kaksi (Eurooppa) tai kolme (Yhdysvallat) nanopartikkeliformulaatiota on hyväksytty markkinoille syövän hoidossa. Ongelmina ovat riittämätön hakeutuminen kohdekudokseen, immunogeenisyys ja nanopartikkelien labiilius. Kokeellisessa osassa tutkitaan in vitro ja hiirillä in vivo 99mTc-leimattujen, PEG-verhoiltujen biotiiniliposomien kaksivaiheista kohdennusta ihmisen munasarjan adenokarsinoomasoluihin. Kohdentamiseen käytetään biotinyloitua setuksimabi-(Erbitux®) vasta-ainetta, joka sitoutuu solujen yli-ilmentämiin EGF-reseptoreihin. Kaksivaiheista kohdennusta verrataan suoraan ja/tai passiiviseen kohdennukseen. Tehokkaampien kuvantamismenetelmien kehitys on vauhdittanut kohdennettujen nanopartikkelien tutkimusta. Isotooppikuvantamista käyttäen pystytään seuraamaan radioleiman jakautumista elimistössä ja kuvantamaan solutasolla tapahtuvia ilmiöitä. Kirjallisuuskatsauksessa perehdytään SPECT- ja PET-kuvantamiseen syövän hoidossa, sekä niiden hyödyntämiseen lääkekehityksessä nanopartikkelien kuvantamisessa. Kyseiset kuvantamismenetelmät erottuvat muista menetelmistä korkean erotuskyvyn, herkkyyden ja helppokäyttöisyyden suhteen. Kokeellisessa osassa 99mTc-leimattujen liposomien distribuutiota hiirissä tutkittiin SPECT-CT-laitteen avulla. Aktiivisuus kasvaimessa, pernassa ja maksassa kvantifioitiin InVivoScope-ohjelman ja gammalaskijan avulla. Tuloksia verrattiin keskenään. In vitro-kokeessa saavutettiin kaksivaiheisella kohdennuksella 2,7- 3,5-kertainen (solulinjasta riippuen) hakeutuminen soluihin kontrolliliposomeihin verrattuna. Kuitenkin suora kohdennus toimi kaksivaiheista kohdennusta paremmin in vitro. In vivo –kokeissa liposomit jakautuivat kasvaimeen tehokkaammin i.p.-annosteltuna kuin i.v.-annosteltuna. Kaksivaiheisella kohdennuksella saavutettiin 1,24-kertainen jakautuminen kasvaimeen (% ID/g kudosta) passiivisesti kohdennettuihin liposomeihin verrattuna. %ID/elin oli kohdennetuilla liposomeilla 5,9 % ja passiivisesti kohdennetuilla 5,4%. Todellinen ero oli siis pieni. InVivoScope:n ja gammalaskijan tulokset eivät korreloineet keskenään. Lisätutkimuksia ja menetelmän optimointia vaaditaan liposomien kohdennuksessa kasvaimeen.

Effects of gender, and SLCO1B1 and CYP7A1 polymorphisms on plasma bile acids in humans and the pharmacokinetics of therapeutic ursodeoxycholic acid

Bile acids are important steroid-derived molecules essential for fat absorption in the small intestine. They are produced in the liver and secreted into the bile. Bile acids are transported by bile flow to the small intestine, where they aid the digestion of lipids. Most bile acids are reabsorbed in the small intestine and return to the liver through the portal vein. The whole recycling process is referred to as the enterohepatic circulation, during which only a small amount of bile acids are removed from the body via faeces. The enterohepatic circulation of bile acids involves the delicate coordination of a number of bile acid transporters expressed in the liver and the small intestine. Organic anion transporting polypeptide 1B1 (OATP1B1), encoded by the solute carrier organic anion transporter family, member 1B1 (SLCO1B1) gene, mediates the sodium independent hepatocellular uptake of bile acids. Two common SNPs in the SLCO1B1 gene are well known to affect the transport activity of OATP1B1. Moreover, bile acid synthesis is an important elimination route for cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme of bile acid production. The aim of this thesis was to investigate the effects of SLCO1B1 polymorphism on the fasting plasma levels of individual endogenous bile acids and a bile acid synthesis marker, and the pharmacokinetics of exogenously administered ursodeoxycholic acid (UDCA). Furthermore, the effects of CYP7A1 genetic polymorphism and gender on the fasting plasma concentrations of individual endogenous bile acids and the bile acid synthesis marker were evaluated. Firstly, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of bile acids was developed (Study I). A retrospective study examined the effects of SLCO1B1 genetic polymorphism on the fasting plasma concentrations of individual bile acids and a bile acid synthesis marker in 65 healthy subjects (Study II). In another retrospective study with 143 healthy individuals, the effects of CYP7A1 genetic polymorphism and gender as well as SLCO1B1 polymorphism on the fasting plasma levels of individual bile acids and the bile acid synthesis marker were investigated (Study III). The effects of SLCO1B1 polymorphism on the pharmacokinetics of exogenously administered UDCA were evaluated in a prospective genotype panel study including 27 healthy volunteers (Study IV). A robust, sensitive and simple HPLC-MS/MS method was developed for the simultaneous determination of 16 individual bile acids in human plasma. The method validation parameters for all the analytes met the requirements of the FDA (Food and Drug Administration) bioanalytical guidelines. This HPLC-MS/MS method was applied in Studies II-IV. In Study II, the fasting plasma concentrations of several bile acids and the bile acid synthesis marker seemed to be affected by SLCO1B1 genetic polymorphism, but these findings were not replicated in Study III with a larger sample size. Moreover, SLCO1B1 polymorphism had no effect on the pharmacokinetic parameters of exogenously administered UDCA. Furthermore, no consistent association was observed between CYP7A1 genetic polymorphism and the fasting plasma concentrations of individual bile acids or the bile acid synthesis marker. In contrast, gender had a major effect on the fasting plasma concentrations of several bile acids and also total bile acids. In conclusion, gender, but not SLCO1B1 or CYP7A1 polymorphisms, has a major effect on the fasting plasma concentrations of individual bile acids. Moreover, the common genetic polymorphism of CYP7A1 is unlikely to influence the activity of CYP7A1 under normal physiological conditions. OATP1B1 does not play an important role in the in vivo disposition of exogenously administered UDCA.